The global landscape of stem cell clinical trials
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Research Article
For reprint orders, please contact: reprints@futuremedicine.com
The global landscape of stem cell clinical trials
Aim: To provide a comprehensive analysis of clinical trials (CTs) listed in worldwide registries involving
new applications for stem cell-based treatments and account for the role of industry. Materials & methods:
We developed a data set of 4749 stem cell CTs up to 2013 in worldwide registries. We defined 1058 novel
CTs (i.e., trials that were not observational in nature; did not involve an established stem cell therapy for
an established indication, such as hematopoietic stem cells for leukemia; and did not investigate supportive
measures). Based on trial descriptions, we manually coded these for eight additional elements. Results: Our
analysis details the characteristics of novel stem cell CTs (e.g., stem cell types being tested, disease being
targeted, and whether interventions were autologous or allogeneic), geotemporal trends, and private
sector involvement as sponsor or collaborator. Conclusion: The field is progressing at a steady pace with
emerging business models for stem cell therapeutics. However, therapeutic rhetoric must be tempered
to reflect current clinical and research realities.
KEYWORDS: business model n cardiac n clinical translation n clinical trial Matthew D Li1,2,
n hematopoietic stem cell n industry n mesenchymal stem cell n neurological n stem cell
Harold Atkins3
mobilization n stem cell therapy
& Tania Bubela*1
1
School of Public Health, 3-279
Stem cell therapies are a category of regenerative contributed to public expectations for stem cell Edmonton Clinic Health Academy,
11405-87 Ave, University of Alberta,
medicine, the promise of which includes innova- therapies, and we have previously noted that Edmonton, AB, T6G 1C9, Canada
tive therapies for organ failure and degenerative proponents need to make a concerted effort to 2
Stanford University, School of
Medicine, 291 Campus Dr, Stanford,
diseases. The first human hematopoietic stem temper claims to reflect current research and CA 94305, USA
cell (HSC) transplant (HSCT) or bone marrow clinical realities [3]. As stated by Daley, “pre- 3
The Ottawa Hospital Research
transplant (BMT) was performed more than mature application runs the risk of high-profile Institute, The Ottawa Hospital General
Campus, 501 Smyth Rd, Ottawa, ON,
50 years ago [1], and it is estimated that more failure that would sully the credibility of this K1H 8L6, Canada
than 1 million HSCTs have been performed still-developing field” [6]. *Author for correspondence:
tbubela@ualberta.ca
since [2]. While stem cell-based therapies have Beyond current therapeutic applications,
become the standard of care for hematological novel therapies in CTs use existing products,
cancers and bone marrow failure states, more such as HSCs, to target an expanded range of
recently stem cell treatments have entered clini- disease categories, for instance, autoimmune
cal practice for treatment of burns and corneal diseases. Alternatively, novel therapies may
regeneration. use new types of stem cells, including mesen-
General optimism exists that stem cell-based chymal stem cells (MSCs), human embryonic
regenerative strategies will be transformative, stem cells (ESCs) or induced pluripotent stem
and there has been a rush to use stem cell prod- cells (iPSCs), or cells derived from any of these
ucts in the clinical realm [3]. This has not only cell types. MSCs are a type of stromal cell that
led to a steady rise in stem cell clinical trials have the potential to differentiate in vitro into
(CTs) for an expanding range of conditions [3], a limited number of cell types, including bone,
but also stem cell tourism in unregulated stem tendon, cartilage and fat, and possess immuno
cell clinics around the world [4] for a wide range modulatory functions [7]. ESCs, contrarily, are
of illnesses [5]. Likely sources of pressure for clin- pluripotent and have the ability to differentiate
ical translation include: patient groups desperate into every cell type in the body. In spite of much
for therapies and cures for currently untreatable public anticipation and policy attention, ESCs
conditions; industry and policy makers eager to have been used in a handful of CTs [3]. Currently,
see a return on substantial investments in stem ESC-derived retinal pigment epithelium cells are
cell research; and researchers, who believe that in trials for rare retinopathies by Advanced Cell
stem cell therapies will offer significant advances Technology (MA, USA) and partner companies
over current treatment or disease management (ClinicalTrials.gov identifiers: NCT01344993,
options. In addition, intense media coverage has NCT01469832 and NCT01345006 [101]).
10.2217/RME.13.80 © Matthew D Li, Harold Atkins Regen. Med. (2014) 9(1), 27–39 ISSN 1746-0751 27
& Tania BubelaResearch Article Li, Atkins & Bubela
In 2013, the first clinical study is commenc- first to give a comprehensive account of the
ing in Japan using iPSCs for six participants global landscape for stem cell therapies, and
with severe age-related macular degeneration [8]. second to account for the role of industry in the
Japanese researcher, Shinya Yamanaka, received field, necessary for robust development beyond
the 2012 Nobel Prize in Physiology or Medicine its academic core.
for the discovery of iPSCs, which are derived
from mature differentiated cells reprogrammed Materials & methods
to become pluripotent. Since the discovery in We searched the term ‘stem cell’ in ClinicalTri-
2006, the field of iPSC research has expanded als.gov [101] and ‘stem cell* NOT NCT0*’ in
rapidly, as evident from the explosion of pub- the WHO’s International Clinical Trials Reg-
lications and patents in the field [9]. However, istry Search Portal [103] to identify trials not
the nature of the iPSC reprogramming process registered with the NIH. The latter included
raises significant safety concerns; the cells are trials from Australia and New Zealand, the
genetically unstable in culture and have the UK, Brazil, China, India, South Korea, Cuba,
potential for long-term tumor formation [10,11]. Germany, Iran, Japan, Africa, Sri Lanka and
Efficacy will also be an issue with questions The Netherlands. Our search for ‘stem cell’ in
about long-term engraftment and function- ClinicalTrials.gov captured more than simply
ality of transplanted cells [6]. Such analysis that phrase. It automatically searched for related
is necessary to inform regulatory policy and terms, including ‘blast cell’, ‘cell progenitors’,
ethical clinical translation, a major concern ‘cells precursor’, ‘cells stems’, ‘hematopoietic
internationally [12]. progenitor cells’, ‘hemocytoblasts’, ‘precursor
Beyond scientific and ethical concerns, the cell’ and ‘progenitor cell’. However, it is impor-
emerging field of stem cell therapeutics faces tant to note that registration does not imply
structural, commercial and economic challenges the supervision of a competent drug regulatory
[13,14]. At present, most stem cell CTs remain authority. While many of the trials we analyzed
early stage and run in academic centers. One of were likely registered with an agency such as the
the greatest challenges lies in engaging industry US FDA, many were not. For example, research
and building multisectorial and interdisciplin- listed for trials in Japan may be registered with
ary teams for large-scale efficacy trials and in the Ministry of Health but not the Pharmaceu-
the wider roll-out of successful therapies. Cor- ticals and Medical Devices Agency, the Japanese
porate investment decisions, the development of equivalent of the FDA, and therefore belong to
viable business models for the delivery of new a separate category of clinical research in the
treatments, and reimbursement decisions by Japane se system. The Biomaster (Japan) and
public and private healthcare payers and insur- Cytori Therapeutics, Inc. (Japan) industry trials
ers will benefit from a detailed analysis of the are examples of ministry-registered trials.
current types of products and services in CTs. Our search strategy had some limitations.
Accordingly, it is time to take stock of novel Some CTs involving stem cells did not explic-
developments in the field, given the advance- itly include ‘stem cell’ or related terms in the
ments in the knowledge of stem cell biology and trial registration entry. For example, Geron
the increasing clinical translational activity. Pre- Corporation’s high-profile CT using ESCs for
vious general reviews have discussed a subset spinal cord injury does not mention ‘stem cell’
of high-profile trials [6,15]. Other trade-related or related terms once in its ClinicalTrials.gov
reviews focus on the regenerative medicine registry entry (ClinicalTrials.gov identifier:
industry as a whole, not specifically on industry- NCT01217008) [101]. Thus, some stem cell tri-
led CTs [102]. By contrast, we have developed als were not captured by our search. In addition,
definitions to identify novel therapeutic appli- our focus was on stem cell CTs, not all CTs that
cations of stem cells and for coding their char- may be categorized as regenerative medicine.
acteristics. Because we have coded each CT For example, engineered tissue products, such as
description manually, our study accurately the Apligraf ® skin graft by Organogenesis (MA,
reflects stem cell types and uses, enabling us to USA), were not included. Apligraf is cultured
identify patterns and trends for trials involving from fibroblasts and keratinocytes. However, a
stem cells and to address industry sponsorship. comparison of our data set to a broader data set
This study represents the first comprehensive of cell therapies compiled by the research group
and systematic analysis of CTs listed in world- of Chris Mason and Emily Culme-Seymour at
wide trial registries involving new applications the London Regenerative Medicine Network
for stem cell-based treatments. It has two aims, (UK) showed good concordance in our two
28 Regen. Med. (2014) 9(1) future science groupThe global landscape of stem cell clinical trials Research Article
CT data sets for all complete years up to the CT coding
end of 2009 [Culme-Seymour E, Pers. Comm.]. The We established a data set that captured all avail-
London group selected cell therapy CTs from able fields from the originating database for
a larger set (n = 17,362 to mid-2010) compiled all CTs included in the data set. The data set
by searching ClinicalTrials.gov in mid-2010 included date, ID number, title, abstract, spon-
using the terms ‘cell’ and ‘therapy’. After filter- sor, location and phase. For novel CTs, based on
ing for relevance (actual cell therapy compared the title and the abstract, each trial was coded
with an enabling technology), the London data for eight elements (Figure 1):
set included 2584 trials, of which 1765 also The goal of the therapy;
occurred in our data set (2804 CTs to 2009 The target of the therapy;
from ClinicalTrials.gov [101]).
The mechanism or process leading to the
We removed nonstem cell-related trials that
disease being treated;
were nevertheless captured by the search and
duplicates (trials registered in more than one The disease/condition targeted;
database) and constructed a data set of CT The stem cell tissue source;
information using all fields from ClinicalTrials. Any stem cell manipulation;
gov whenever possible. We limited the data The graft donor source;
set to CTs registered in either registry before
1 January 2013. Stem cell type.
Wherever possible, we categorized the
Definition of novel CT stem cells used. Three coders were trained by
We established criteria to identify those CTs H Atkins to code the data set. One (MD Li)
testing novel stem cell therapies. These novel coded all trials and two worked during differ-
applications of stem cell therapies involved: ent time periods, prior to 2011 and post 2011.
The use of stem or progenitor cells to stimu- Where discrepancies and questions occurred,
late nonhematopoietic organ regeneration these were resolved either through discussion
(e.g., limbal stem cells for cornea regeneration among the coders and/or verified through dis-
or HSCs for cardiac repair); cussions with H Atkins. If further information
was required for accurate coding, we conducted a
The use of agents to stimulate stem or pro-
keyword Google™ search (e.g., to determine the
genitor cell action for regenerative or thera-
identity or characteristics of a therapeutic agent
peutic purposes (note that CTs on agents
identified only by proprietary title in the registry
targeting cancer stem cells were excluded);
entry). Industry trials were those that, in the
The use of established HSCT procedures for registry data field for sponsor and collaborator,
novel indications (i.e., HSCT for autoimmune indicated a company name. We then searched
or congenital diseases); for each company name in the Orbis – Bureau
The use of novel agents or processes for stem van Dijk database for financial data, if available,
or progenitor cell mobilization for therapeutic in September 2013 [104].
purposes;
Results
The use of gene therapy or other ex vivo mod-
The characteristics of novel CTs
ified stem or progenitor cells (note that adop-
Our search yielded 4749 CTs registered before
tive cell therapies for targeting cancers were
1 January 2013. Based on our definition (see
not classified as novel).
‘Materials & methods’ section), we classified
We excluded CTs that: 1058 (22%) as novel applications of stem cell
therapy (Figure 1; also see Supplementary M aterial
Were observational in nature (e.g., only mea-
online at w w w.futuremedicine.com/doi/
suring circulating endothelial precursor cells
suppl/10.2217/rme.13.80 for detailed descrip-
after exercise);
tions of the characteristics of the 1058 novel
Involved an established stem cell therapy for CTs). The proportion of novel CTs increased
an established indication (e.g., HSCT for from 2004 to 2011 (Figure 2). The bulk of the
leukemia); or increase has occurred since 2006 due to CTs
using MSCs. The majority (87%) of novel CTs
Investigated supportive measures surround- were in early-phase testing (Supplementary Figure 1).
ing a stem cell therapy (e.g., antibiotics to Novel CTs most commonly had a regenera-
prevent infection in HSCT recipients). tive therapeutic goal (87%), and this subset
future science group www.futuremedicine.com 29Research Article Li, Atkins & Bubela
Database of clinical trials (n = 4749)
Non-novel (n = 3691)
Novel (n = 1058)
Principle disease/condition targeted Stem cell tissue source†
Goal of stem cell therapy • Cardiovascular disease (278) • Bone marrow (439)
• Regeneration (916) • Neurological disease (169) • Peripheral blood (170)
• Cell therapy (nonregenerative) (126) • Cancer (97) • No sampling (112)
• Gene therapy (96) • Liver disease (67) • Umbilical cord (99)
• Stem cell collection/mobilization (30) • Bone condition (65) • Unspecified (95)
• Bioscaffold (15) • Other (56) • Adipose tissue (92)
• Immunotherapy (13) • Immunodeficiency and other nonmalignant • Eye (16)
hematologic conditions (49) • Brain (12)
• Gastrointestinal disease (46) • Placenta (9)
• Cartilage disease (45) • Heart (6)
Target of stem cell therapy‡ • Systemic rheumatological disease (45) • Embryo (6)
• Immune system (260) • Diabetes (43)
• Heart (197) • Eye disease (39)
• Marrow (157) • Skin condition (19) Stem cell manipulation
• CNS (125) • Organ transplant-associated (18) • Cultured (441)
• Vascular system (90) • Lung disease (15) • Purified (236)
• Kidney condition (8) • Drug treatment (95)
• Gene modified (79)
• None (115)
Stem cell type
Mechanism of disease being treated • Other (49)
• Hematopoietic (whole marrow, CD34+,
• Injury or degeneration (400) • Unspecified (43)
CD133+ or mononuclear fractions) (432)
• Ischemia (274)
• Mesenchymal (432)
• Drug- (chemotherapy) or radiation-induced
• Endothelial progenitor cells (69)
damage (224) Graft donor source
• Other (69)
• Immune attack (142) • Autologous (594)
• Neural (22)
• Congenital or inherited disease (79) • Allogeneic (305)
• Unspecified (20)
• Neoplasia (52) • Autologous and allogeneic (8)
• Limbal (16)
• Infection (10) • No stem cell graft (118)
• Embryonic (6)
• Healthy volunteers (10) • Unspecified (33)
• Cardiac (6)
Figure 1. Coding method for all stem cell clinical trials to the end of 2012. Databases searched were the WHO International
Clinical Trials Registry Platform [103] and ClinicalTrials.gov [101] . The number of clinical trials coded into each category are in parentheses.
Some clinical trials were coded for more than one category.
†
See Supplementary Table 1 for full list.
‡
See Supplementary Table 2 for full list.
of CTs primarily targeted tissue injury from 2009, although autologous uses are still more
degeneration and ischemia (Figure 1). numerous (Figure 3).
The majority of stem cell products used were
obtained from a hematopoietic source such Diseases or conditions addressed by
as the bone marrow (41%), peripheral blood novel stem cell CTs
(16%) or umbilical cord (9%). An increas- Unlike the majority of CTs that primarily
ing number of trials tested stem cell products addressed hematological and other cancers, the
derived from adipose tissue (9%; Supplementary focus of novel stem cell CTs, with respect to dis-
Table 1). Forty-two percent of CTs used prod- ease indication, is cardiovascular disease (Figure 1).
ucts produced by in vitro cell culture, mainly Nevertheless, the immune system remains the
MSCs. Other trials used stem cell products most common target of stem cell therapies
that had been purified (22%), manipulated for various disease indications, which include
with drug treatments (7%) or genetically cancers, graft-versus-host disease (GvHD) and
modified (7%; F igur e 1). Since 2004, there other nonmalignant hematologic conditions, as
has been a steady number (7–15 per year) of well as autoimmune diseases such as multiple
CTs using interventions such as drug treat- sclerosis, Crohn’s disease and Type 1 diabetes.
ments and exercise for in vivo mobilization or Increasing numbers of CTs targeted neurological
activation of stem cells, usually without stem diseases, while CTs for liver disease, bone and
cell harvest or treatment. Notably, the use of cartilage conditions, diabetes, and eye diseases
allogeneic products has increased rapidly since remained rare (The global landscape of stem cell clinical trials Research Article
diseases and conditions were reflected in the Figure 5B). In Europe, the dominant countries for
tissues targeted by the CTs (Supplementary Figure 2 novel stem cell CTs are Spain, the UK, and Ger-
& Supplementary Table 2). The Supplementary M aterial many, but there are also many in Italy, France,
presents detailed summaries of the CTs in each The Netherlands and Belgium (Figure 5C).
disease category, including the extent of industry
engagement within each disease category. Industry engagement in novel stem
Development of cardiovascular indications cell CTs
were in the most advanced stage of testing, with Industry involvement was reported in 265 (25%)
24% of CTs beyond Phase II, compared with novel CTs, either as principal sponsor or collabo-
just 13% of all CTs. rator. This does not include Clinical Research
Organizations (CROs) responsible for running
International landscape of novel many trials. The extent of industry involvement
stem cell CTs has grown rapidly since 2004 (Figure 6), and our
The registration and initiation of novel CTs has study likely underestimated its extent; we only
expanded rapidly since 2004 (Figure 4). In 2008, captured sponsorships or collaborations that
the number of novel trials in Asia, mainly in were reported in the CT databases. Internation-
China, but also in South Korea, India and Japan, ally, commercial sponsors were involved in more
surpassed the number in the USA and Europe. than 25% of novel CTs in South Korea, Malay-
This geographic shift continues to become more sia, Canada, Israel, India, Australia and the USA
pronounced. An increasing number of trials are (all countries with >5 CTs; Figure 5). The USA
taking place in Australia, Brazil, India, South had the greatest absolute number of CTs with
Korea, Iran and Israel (Figure 5). Countries in industry involvement. The US states reporting
Asia, the Middle East and South America host the most industry involvement as a proportion
a greater proportion of novel CTs (Figure 5A). In of novel CTs were Louisiana, California, North
the USA, states with policies and funding to Carolina, Pennsylvania and Massachusetts (all
support stem cell research also dominate CTs. states with >5 CTs; Figure 5B). Indeed, in Cali-
States with more than 100 total CTs include fornia, nearly 50% of novel CTs had industry
Maryland (mainly NIH CTs), California, Texas, involvement. However, most CTs globally with
New York, Washington, Minnesota, Illinois and industry involvement were in an early (Phase I,
Massachusetts. Maryland, Illinois, California I/II and II) stage (Supplementary Figure 2). As a pro-
and Texas have the most novel CTs (>30 CTs; portion of novel CTs, industry was most heavily
600
Novel clinical trials (involving MSCs)
Novel clinical trials (not involving MSCs)
500
Non-novel clinical trials
400
Clinical trials (n)
300
200
100
0
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
Start year
Figure 2. Time trends in 4749 stem cell clinical trials, globally. The proportion of clinical trials
classified as novel applications of stem cell therapies increased from 2004 to 2011. Within novel
clinical trials (n = 1058), most of the increase since 2006 was due to trials using MSCs. The decrease
in clinical trials in 2012 may be due to a lag in trial registration.
MSC: Mesenchymal stem cell.
future science group www.futuremedicine.com 31Research Article Li, Atkins & Bubela
100
Allogeneic
90
Autologous
80
Autologous and allogeneic
70
No graft product
Clinical trials (n)
60 Unspecified
50
40
30
20
10
0
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
Start year
Figure 3. Transplant type start dates for novel clinical trials (n = 1058). Allogeneic stem cell
clinical trials increased rapidly from 2008, a few years behind autologous stem cell clinical trials.
engaged in gastrointestinal diseases (48%), lung pharmaceutical companies’ (e.g., Pfizer, Takeda
disease (40%), cartilage disease (36%), neuro- [Japan] and Italia Farmaceutici [Italy])activity
logical diseases (28%), diabetes (26%) and bone in the stem cell field remains focused upon
conditions (25%). biological and small molecules for stem cell
The majority of companies involved were mobilization and/or activation (Supplementa ry
small-to-medium-sized, privately held biotech- Table 3). Novartis Pharmaceuticals (NJ, USA)
nology companies with fewer than 80 employ- stands out in conducting a trial using ex vivo-
ees engaged in one or two CTs (Supplementary expanded umbilical cord blood stem cells for
Table 3). Some companies focused on one or two hematological malignancies (see the Supplementary
diseases, including Advanced Cell Technology M aterial for detailed summaries of the industry
and Mesoblast (Australia), while others limited trends in each disease category).
their trials to a discipline such as cardiovascular
diseases (e.g., Capricor [CA, USA] and Cardio3 Discussion
BioSciences [Belgium]), stroke (e.g., ReNeuron Current state of translational stem
[UK], Stem Cell Therapeutics [ON, Canada] cell research
and Sanbio [CA, USA]), and cartilage or bone Our results show that the majority of all reg-
repair (e.g., Mesoblast, NuVasive® [CA, USA] istered stem cell CTs continue to address uses
and Orthofix [TA, USA]). An emerging busi- of HSCs derived from bone marrow, umbilical
ness model, linked to the rise in MSC CTs, is cord blood or peripheral blood, for conditions
the allogeneic use of a single stem cell product traditionally associated with BMT. However,
for a broad range of conditions (Supplementary even in the well-established HSC field, a small
Table 3). Some regenerative medicine biotechnol- but growing number of trials are for novel
ogy firms, such as Athersys (OH, USA), Osiris indications, such as multiple sclerosis, Type 1
(MD, USA) and Medipost (South Korea) were diabetes and other autoimmune diseases.
engaged in trials for multiple, unrelated condi- There is increasing activity in clinical test-
tions. Smaller biotechnology companies have ing of MSCs derived from bone marrow or
engaged the largest players in the pharmaceu- adipose tissue. Major gaps in knowledge exist
tical industry in the joint ventures to produce in the fundamental understanding of: the dura-
allogeneic stem cell products (e.g., Gamida tion of their survival after transplantation; their
Cell [Israel]–Teva [Israel] joint venture using impact on unaffected tissues and organs; and
StemEx® for hematological malignancies and the phenot ypic changes they undergo in the tar-
Athersys–Pfizer (NY, USA) using MultiStem® get tissue. Daley has raised concerns over this
for ulcerative colitis) as the latter are focused expansion of MSC trials into “indications where
on product development for broad-based the clinical hypotheses are more speculative,
use. Within this paradigm, more traditional the therapeutic mechanisms are incompletely
32 Regen. Med. (2014) 9(1) future science groupThe global landscape of stem cell clinical trials Research Article
defined, and in some instances the preclinical and marketed as Prochymal® have received a
evidence is highly contentious” [6]. Despite these notice of compliance with conditions in Canada
gaps, MSCs are being tested around the globe for the treatment of pediatric steroid-refractory
for a wide range of conditions. Indeed, in our GvHD, which represents the first stem cell bio-
analysis, MSCs were the predominant stem cell logic licensed by a national regulatory agency
used in novel clinical applications. Outside of [105]. Prochymal is being evaluated in Phase III
North America and Europe, MSCs were used CTs for GvHD and Crohn’s disease, and is the
in an even higher proportion of novel trials of only stem cell product currently designated by
stem cells. We have previously speculated that the FDA as both an orphan drug and a fast-
North America and Europe are dominant in track product [106]. Furthermore, Phase II trials
trials extending the traditional use of HSCs are ongoing in chronic obstructive pulmonary
because of the existing BMT infrastructure. By disease, Crohn’s disease, GvHD, myocardial
contrast, this infrastructure is underdeveloped infarction and Type 1 diabetes.
in many regions that are conducting proportion- Cardiovascular diseases are the leading con-
ately more novel stem cell CTs using MSCs [3,16]. dition for registration of novel stem cell CTs.
Some trials of MSCs are being conducted These mainly attempted to regenerate the heart
to examine their regenerative or reparative or peripheral vascular system through various
potential including Phase II trials for diabetes, stem cell infusions or mobilization of endo
pulmonary hypertension and chronic obstruc- genous stem cells. Regarding trials addressing
tive pulmonary disease (COPD) [17]. However, cardiac conditions in particular, overall safety
126 CTs involving MSCs were attempting to appears generally favorable [21,22]. However,
exploit their immunomodulatory properties, the limited clinical data suggest that few donor
most commonly for treating GvHD. The under- cells remain in the heart following transplan-
lying mechanism for these properties is not fully tation [22]. Only modest improvements in car-
understood but is based on observations that diac function after myocardial infarction have
MSCs interfere with immunological assays been reported using a range of cells, including
and modulate classes of immune cells [15]. This MSCs, skeletal myoblasts, bone marrow cells,
observation has led to MSC CTs for autoim- peripheral blood cells [23] or autologous cardiac
mune diseases such as Crohn’s disease [18], multi stem cells derived from heart biopsies with no
ple sclerosis and systemic lupus erythematosus, clear choice of optimal cell type emerging [22].
as well as diabetes [19]. Efficacy outcomes are dif- A recent update of the 2008 Cochrane Review
ficult to interpret because of variable pre-MSC of 33 trials addressed whether bone marrow-
transplant treatment regimens, nonstandard- derived stem cells could prevent damage caused
ized outcome measures and lack of long-term by a heart attack. It concluded that there is mod-
follow-up [18,20]. However, allogeneic-cultured erate long-term improvement of heart function
MSCs produced under proprietary conditions and reduction of scar size, but lack of sufficient
80
USA
70
Asia
60 South and Central America
Clinical trials (n)
Europe
50
Middle East
40
30
20
10
0
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
Start year
Figure 4. Regional start dates for novel clinical trials (n = 1058).
future science group www.futuremedicine.com 33Research Article Li, Atkins & Bubela
20 22
11
157 466
226 12 200
498 63
124 158
33 859 112 181
340 215
586 78 57
27 58 42
10
32
69
22
124 6
20
5 3 9
10 31
207 139 221
79 45 95 1
19 157 217 7
19 90 48 7
2 19 69 355 1
20 125 1
2
137 3 6 152 44
10 8 35 11 68 14 3
340 14
90 6 124 158
9 4 8 5
4 6 50 4
249 1 57
9 78
33 1
8
6
Figure 5. Geographic location of 4749 stem cell clinical trials globally. Illustrates those (A) globally, and in (B) the USA by state,
and (C) Europe and the Middle East by country. The total number of trials is indicated in each blue pie chart, with the proportion of
novel trials, representative of the future of regenerative medicine, indicated in red. (A) Pie charts without numbers denote
regions/countries with fewer than ten clinical trials.
evidence to evaluate long-term survival rates [24], frequency of application [22,23,25]. The task force
although this may not be a relevant end point of the European Society of Cardiology for Stem
when the cell therapy is not directed at reversal Cells and Cardiac Repair recently received fund-
of atherosclerosis or infarct prevention. ing from the EU to conduct a large-scale trial
Criticism has arisen from the perceived lack of with 3000 patients using standardized treatment
rigor and absence of controlled trials. Increased procedures [24]. It is expected that, as the field
rigor requires the involvement of homogeneous matures, there will be efforts to increase harmo-
patient populations, and consistency in cell nization among international trial sites and to
phenotyping practices, dosing, delivery and conduct larger double-blind, placebo-controlled
34 Regen. Med. (2014) 9(1) future science groupThe global landscape of stem cell clinical trials Research Article
studies. Such efforts will be required to convince discontinued its stem cell program [28]. We agree
patients, the medical community and regulators with Daley’s assessment that, while there are
of the efficacy of stem cell therapies, and lead promising advances, routine clinical use of stem
to increased industry participation and invest- cell therapy for neurological conditions is still
ment in the field, and ultimately to convince optimistically many decades away [6].
reimbursement agencies that such therapies are Clinical use of pluripotent stem cells has
cost effective relative to current available and shifted to ophthalmic indications. Advanced
other new competing treatments. Cell Technology has reported on the safety of
Similar concerns have been expressed for retinal pigment epithelium cells derived from
stem cell treatments of diseases of other organs, ESCs transplanted into patients with advanced-
although research efforts are focused at the stage Stargardt’s macular dystrophy and dry
beginning of the path towards clinical applica- age-related macular degeneration [29]. Simi-
tion. The pressure for rapid testing and imple- larly, ESCs can be cultured to ‘corneal-like cells’
mentation are most pronounced for neurological in vitro [30,31]. Adult limbal stem cells maintain
conditions because, for many diseases, there is and regenerate the corneal epithelium, and while
a lack of treatment options [3]. Many trials are limbal stem cell transplantation is currently used
still in very early stages and run in academic to regenerate damaged corneas in certain situa-
centers [26]. Progress is hampered by the lack of tions, a source of limbal stem cells is not always
funding streams beyond the public sector [27]. available. ESC-derived limbal stem cells may
Optimistically, overall, 28% of novel neurologi- provide an alternative source. Finally, advances
cal CTs indicated industry involvement, which in directed differentiation of pluripotent stem
increases to nearly 50% in the USA, and over cells into retinal cell lineages, combined with
50% in India and South Korea. On the other iPSC production and research on in vitro cre-
hand, StemCells Inc. (CA, USA) discontinued ation of 3D retinas, offers the promise of vision
its trial for a rare neurological condition, Bat- restoration to patients with retinal diseases [32].
ten’s disease, because of problems with recruit-
ment [6]; the company’s current focus is in Beyond the academy: industry
Pelizaeus–Merzbacher disease, a rare genetic engagement in stem cell CTs
leukodystrophy. The highly publicized Geron Our analysis of industry-sponsored CTs indi-
(CA, USA) trial using oligodendrocyte pro- cates that a few potential business models are
genitors derived from human ESCs for remy- emerging for stem cell therapies. Private and
elination of damaged axons following spinal public biobanks have been established to store
cord injury was first delayed by the FDA over and supply umbilical cord blood-derived stem
concerns of cyst formation in animal models cells mainly for pediatric HSCT. Stem cell
and was then halted in November 2011, after biobanks have been set up and networked in
only four trial subjects were treated, when Geron a variety of regions to enhance access to ESC
200
180 Industry
Public
160
140
Clinical trials (n)
120
100
80
60
40
20
0
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
Start year
Figure 6. Industry and publicly funded novel stem cell clinical trials, globally.
future science group www.futuremedicine.com 35Research Article Li, Atkins & Bubela
and iPSC lines. However, most still only supply sources. Registries have limitations in terms
research-grade materials. of scope and language of coverage, and the
The point-of-care device business model, reporting of international trials is based on vol-
which builds on traditional applications of untary and specific registration. Furthermore,
HSC transplantation where a stem cell labora- registration is not indicative of supervision by a
tory is located in academic centers or hospitals, competent drug regulatory authority. Although
is based on companies that produce devices beyond the scope of this analysis, it is important
that manipulate the cells on site for immediate to note that companies engaged in providing
use. An example is Cytori Therapeutics’ Celu- unproven stem cell therapies in clinics linked to
tion® device, which “automates and standard- ‘stem cell tourism’ register CTs as a marketing
izes the extraction, washing and concentration tactic or as a method to recruit patients. Such
of autologous adipose-derived cells, which can registration adds a veneer of legitimacy to the
then be reimplanted back into the same patient CT and companies, such as Adistem (China),
in a single surgical procedure” [13]. Where cells Beike Biotechnology (China) and subsidiaries
are processed off site or where more extensive TCA Cellular Therapy (LA, USA), RNL Bio
manipulation is involved, access to facilities (South Korea) and Bioheart (FL, USA), have
meeting GMP standards and clinical grade all registered CTs (Supplementary Table 3). Registries
materials will be limiting [33]. The National might be improved by indicating the competent
Heart Lung and Blood Institute of the NIH is regulatory authority and research ethics board
remedying the gap in appropriate manufactur- overseeing the trial.
ing facilities by supporting Production Assis-
tance for Cellular Therapies (PACT) and its Conclusion & future perspective
five current GMP facilities in the USA. PACT’s Our study presents the most comprehensive
purpose is to provide product development and account of the global stem cell CT landscape
manufacturing assistance to researchers who to date. It is evident from our analysis that
require current GMP facilities but lack such the breadth and number of CTs is increasing
capacity [34]. PACT also assists in early-stage around the globe, but that the whole endeavor
CTs and provides technology transfer support is proceeding with caution. The large number
for clinical-scale production. of Phase I trials demonstrates that the field is
Biotechnology companies are also engaged in just starting to move from preclinical research
the development of cell therapies that allow for into the clinic. The focus has largely been on
an ‘off-the-shelf ’ approach [14,33]. This business the safety of these treatments; however, con-
model is commercially attractive, as a common sensus is emerging that large-scale safety con-
cell product could be used to treat large patient cerns have not arisen, at least in the short term
populations, generating a steady revenue stream. for many cultured stem cell types. The safety
In this approach, therapies are standardized, of pluripotent stem cells is still an unknown
allowing for scaled manufacturing and bulk quantity given that they are relatively unstable
production. However, the allogeneic nature in culture and there has been limited exposure
of these products introduces immunological in human trials. Therefore, clinical translation
issues that will certainly hinder the adoption should proceed with caution and with sufficient
of this model [35]. In light of this concern, it is regulatory oversight.
not surprising that 63% of novel allogeneic CTs Future research should expand our approach
involved MSCs, which have immunosuppres- to other categories of regenerative medicine,
sive properties. Similar off-the-shelf approaches such as cell therapies, immunotherapy and tissue
are being used by traditional pharmaceutical engineering; give a more comprehensive account
and biotechnology companies engaged in the of industry CTs by searching websites and press
development of drugs that act on stem cells. releases of regenerative medicine companies and
These small-molecule drugs target stem cells, trade publications; and identify and analyze
causing them to mobilize and/or differentiate published CT results to more accurately account
in vivo. Although this model allows for scal- for progress in the field. There is, as of now,
ability and the creation of blockbuster drugs limited evidence of efficacy for novel stem cell
with high margins, few firms are as yet actively therapeutic applications. It is unclear whether
engaged in the field [33]. these preliminary results from current CTs will
Our study likely under-represented industry lead to more public or private investment that
sponsorship of CTs because it is reliant solely on will spearhead definitive multicenter CTs that
global CT registries and did not canvass trade demonstrate the regenerative potential of stem
36 Regen. Med. (2014) 9(1) future science groupThe global landscape of stem cell clinical trials Research Article
cells trials or whether it will be back to the Financial & competing interests disclosure
bench. The field is progressing at a steady pace, This study was funded by the Stem Cell Network Strategic
but the therapeutic rhetoric must be tempered Core Grant (to T Bubela and H Atkins) and a Stem Cell
to reflect current clinical and research realities. Network Strategic Core Grant: Public Policy & ELSI (to
T Bubela and H Atkins). In 2011, MD Li was awarded
Author contributions an Alberta Innovates Health Solutions Summer
T Bubela and H Atkins designed the research questions; Studentship and a Stem Cell Network Social Sciences
MD Li and H Atkins developed the final clinical trial Summer Studentship. H Atkins is a stem cell transplant
coding frame and completed the data analysis; and MD Li, physician at the Ottawa Hospital Research Institute and
H Atkins and T Bubela drafted the manuscript and is currently the principal investigator of a clinical trial
approved the final version for publication. using hematopoietic stem cell transplantation for multiple
sclerosis. The authors have no other relevant affiliations
Acknowledgements or financial involvement with any organization or entity
The authors would like to thank M Hafez for development with a financial interest in or financial conflict with the
of the initial coding frame and coding clinical trials to subject matter or materials discussed in the manuscript
2009, M Bieber for technical assistance with mapping and apart from those disclosed.
data management, and L Dacks and M Fung for research No writing assistance was utilized in the production of
assistance. this manuscript.
Executive summary
Rationale & aims
Stem cell-based regenerative medicine strategies are expected to be transformative for organ failure and degenerative diseases. As
translational activity increases, it is time to take stock of novel and global developments in the field of translational stem cell
research.
This analysis aims to give a comprehensive account of the global landscape for stem cell therapies and to account for the role of
industry in the field, necessary for robust development beyond its academic core.
Materials & methods
We developed a data set from a search of the term ‘stem cell’ (and synonyms) in ClinicalTrials.gov and ‘stem cell* NOT NCT0*’ in the
WHO’s International Clinical Trials Registry Search Portal, and coded these according to criteria we developed to identify clinical trials
(CTs) testing novel stem cell therapies.
Characteristics of novel stem cell CTs
Since 2006, an increasing number and proportion of novel CTs have tested mesenchymal stem cells derived from bone marrow or
adipose tissue. A growing number of trials use hematopoietic stem cells for novel indications, such as autoimmune diseases.
Cardiovascular diseases are the main target of novel CTs.
Most novel trials remain focused on safety, and there is as yet limited evidence of efficacy for many indications.
International landscape
The registration of novel stem cell CTs is expanding rapidly around the world, particularly in east Asia, but also in Australia, Brazil,
India, Iran and Israel.
Industry involvement
Industry involvement has grown rapidly since 2004 and was reported in a quarter of novel CTs, either as principal sponsor or
collaborator. This is likely an underestimate because we only captured sponsorships or collaborations that were reported in the CT
databases. Industry was, proportionally, most heavily engaged in gastrointestinal diseases (48%), lung disease (40%), cartilage
disease (36%), neurological diseases (28%), diabetes (26%) and bone conditions (25%).
A few potential business models are emerging for stem cell therapies, notably ‘point-of-care devices’ and ‘off-the-shelf’ models.
The majority of companies involved were small to medium-sized, privately held biotechnology companies.
Conclusion
The field is progressing at a steady pace, but the therapeutic rhetoric must be tempered to reflect current clinical and research
realities. It is unclear whether results from current trials will lead to more public or private investment that will spearhead definitive
multicenter CTs that demonstrate the regenerative potential of stem cells trials or whether it will be back to the bench.
Future perspective
Future research should expand our approach to other categories of regenerative medicine, such as cell therapies, immunotherapy
and tissue engineering; give a more comprehensive account of industry CTs by searching websites and press releases of regenerative
medicine companies and trade publications; and identify and analyze published CT results to more accurately account for progress in
the field.
future science group www.futuremedicine.com 37Research Article Li, Atkins & Bubela
10 Pera MF. The dark side of induced 24 Mummery CL, Lee RT. Is heart regeneration
Open Access
pluripotency. Nature 471(7336), 46–47 on the right track? Nat. Med. 19(4), 412–413
This work is licensed under the Creative Commons (2011). (2013).
Attribution-NonCommercial 3.0 Unported License.
11 Zwaka TP. Stem cells: troublesome 25 Lawall H, Bramlage P, Amann B. Treatment
To view a copy of this license, visit http:// memories. Nature 467(7313), 280–281 of peripheral arterial disease using stem and
creativecommons.org/licenses/by-nc-nd/3.0/ (2010). progenitor cell therapy. J. Vasc. Surg. 53(2),
12 Hyun I, Lindvall O, Ahrlund-Richter L et al. 445–453 (2011).
References New ISSCR guidelines underscore major 26 Bednar MM, Perry A. Neurorestoration
Papers of special note have been highlighted as: principles for responsible translational stem therapeutics for neurodegenerative and
n of interest
cell research. Cell Stem Cell 3(6), 607–609 psychiatric disease. Neurol. Res. 34(2),
nn of considerable interest
(2008). 129–142 (2012).
1 Appelbaum FR. Hematopoietic-cell nn Key statement of principles from the 27 Aboody K, Capela A, Niazi N, Stern JH,
transplantation at 50. N. Engl. J. Med. Temple S. Translating stem cell studies to the
International Society for Stem Cell
357(15), 1472–1475 (2007). clinic for CNS repair: current state of the art
Research on the responsible translation of
2 Thomas ED, Lochte HL Jr, Lu WC, Ferrebee stem cell research. and the need for a Rosetta stone. Neuron
JW. Intravenous infusion of bone marrow in 70(4), 597–613 (2011).
13 Mason C, Brindley DA, Culme-Seymour EJ,
patients receiving radiation and 28 Baker M. Stem-cell pioneer bows out. Nature
Davie NL. Cell therapy industry: billion
chemotherapy. N. Engl. J. Med. 257(11), 479(7274), 459 (2011).
dollar global business with unlimited
491–496 (1957).
potential. Regen. Med. 6(3), 265–272 (2011). 29 Schwartz SD, Hubschman JP, Heilwell G
3 Bubela T, Li MD, Hafez M, Bieber M, et al. Embryonic stem cell trials for macular
14 Rao MS. Funding translational work in
Atkins H. Is belief larger than fact: degeneration: a preliminary report. Lancet
cell-based therapy. Cell Stem Cell 9(1), 7–10
expectations, optimism and reality for 379(9817), 713–720 (2012).
(2011).
translational stem cell research. BMC Med.
15 Trounson A, Thakar RG, Lomax G, 30 Ahmad S. Concise review: limbal stem cell
10, 133 (2012).
Gibbons D. Clinical trials for stem cell deficiency, dysfunction, and distress. Stem
4 Regenberg AC, Hutchinson LA, Schanker B, Cells Transl. Med. 1(2), 110–115 (2012).
therapies. BMC Med. 9, 52 (2011).
Mathews DJ. Medicine on the fringe: stem
Selective review of key clinical trials for 31 Osei-Bempong C, Figueiredo FC, Lako M.
cell-based interventions in advance of n
stem cell therapies using a range of stem cell The limbal epithelium of the eye – a review
evidence. Stem Cells 27(9), 2312–2319
of limbal stem cell biology, disease and
(2009). types for a range of conditions.
treatment. BioEssays 35(3), 211–219 (2013).
5 Lau D, Ogbogu U, Taylor B, Stafinski T, 16 Gratwohl A, Baldomero H, Frauendorfer K
32 Tibbetts MD, Samuel MA, Chang TS,
Menon D, Caulfield T. Stem cell clinics et al. Hematopoietic stem cell
Ho AC. Stem cell therapy for retinal disease.
online: the direct-to-consumer portrayal of transplantation: a global perspective. JAMA
Curr. Opin. Ophthalmol. 23(3), 226–234
stem cell medicine. Cell Stem Cell 3(6), 303(16), 1617–1624 (2010).
(2012).
591–594 (2008). 17 Weiss DJ, Bersoncello I, Borok Z, Kim C
33 Martin PA, Coveney C, Kraft A, Brown N,
nn Key empirical study on stem cell tourism et al. Stem cells and cell therapies in lung
Bath P. Commercial development of stem cell
clinics, the conditions for which they biology and lung diseases. Proc. Am. Thorac.
technology: lessons from the past, strategies
market therapies and the evidence base for Soc. 8(3), 223–272 (2011).
for the future. Regen. Med. 1(6), 801–807
those therapies. 18 Dalal J, Gandy K, Domen J. Role of (2006).
6 Daley GQ. The promise and perils of stem mesenchymal stem cell therapy in Crohn’s
disease. Pediatr. Res. 71(4 Pt 2), 445–451
n Key article on the challenges facing the
cell therapeutics. Cell Stem Cell 10(6),
(2012). commercial development of stem cell
740–749 (2012).
technologies that builds upon a large
nn Review of the clinical trial environment for 19 Barcala Tabarrozzi AE, Castro CN, Dewey
empirical study of the sector.
stem cell therapies. Comments on the RA, Sogayar MC, Labriola L, Perone MJ.
Cell-based interventions to halt 34 Reed W, Noga SJ, Gee AP et al. Production
difficulties in obtaining unequivocal
autoimmunity in Type 1 diabetes mellitus. Assistance for Cellular Therapies (PACT):
evidence for robust clinical benefit, the rise four-year experience from the United States
Clin. Exp. Immunol. 171(2), 135–146 (2013).
of stem cell clinics, and the challenges and National Heart, Lung, and Blood Institute
technical barriers for achieving meaningful 20 Tyndall A. Application of autologous stem
(NHLBI) contract research program in cell
clinical impact. cell transplantation in various adult and
and tissue therapies. Transfusion 49(4),
pediatric rheumatic diseases. Pediatr. Res.
7 Dominici M, Le Blanc K, Mueller I et al. 786–796 (2009).
71(4 Pt 2), 433–438 (2012).
Minimal criteria for defining multipotent 35 von Tigerstom B. The Food and Drug
mesenchymal stromal cells. The International 21 Williams AR, Hare JM. Mesenchymal stem
Administration, regenerative sciences, and
Society for Cellular Therapy position cells: biology, pathophysiology, translational
the regulation of autologous stem cell
statement. Cytotherapy 8(4), 315–317 (2006). findings, and therapeutic implications for
therapies. Food Drug Law J. 66(4), 479–506
cardiac disease. Circ. Res. 109(8), 923–940
8 Cyranoski D. Stem cells cruise to clinic. (2011).
(2011).
Nature 494(7438), 413 (2013).
22 Rosenweig A. Cardiac regeneration. Science
9 Mathews DJ, Cook-Deegan R, Bubela T. 338(6114), 1549–1550 (2012).
Patents and misplaced angst: lessons for Websites
translational stem cell research from 23 Ptaszek LM, Mansour M, Ruskin JN, Chien
101 NIH. ClinicalTrials.gov.
genomics. Cell Stem Cell 12(5), 508–512 KR. Towards regenerative therapy for cardiac
http://clinicaltrials.gov
(2013). disease. Lancet 379(9819), 933–942 (2012).
(Accessed 12 October 2013)
38 Regen. Med. (2014) 9(1) future science groupThe global landscape of stem cell clinical trials Research Article
102 Alliance for Regenerative Medicine. ARM http://apps.who.int/trialsearch www.medicalnewstoday.com/articles/245704.
2013 Regenerative Medicine Annual Report. (Accessed 12 October 2013) php
http://alliancerm.org/news/download-must- 104 Bureau Van Dijk. Orbis. (Accessed 12 October 2013)
have-industry-report www.bvdinfo.com 106 Osiris Therapeutics, I (2013). Therapeutics.
(Accessed 12 October 2013) (Accessed 12 October 2013) Prochymal.
103 WHO. International Clinical Trials Registry 105 Rattue P. Prochymal – First Stem Cell Drug www.osiris.com/therapeutics.php
Platform. Approved. Medical News Today (2012). (Accessed 12 October 2013)
future science group www.futuremedicine.com 39You can also read
